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@ARTICLE{Rhle:157525,
      author       = {A. Rühle$^*$ and A.-L. Grosu$^*$ and N. Wiedenmann$^*$ and
                      M. Mix and R. Stoian$^*$ and G. Niedermann$^*$ and D.
                      Baltas$^*$ and M. Werner$^*$ and W. A. Weber and G.
                      Kayser$^*$ and N. H. Nicolay$^*$},
      title        = {{H}ypoxia dynamics on {FMISO}-{PET} in combination with
                      {PD}-1/{PD}-{L}1 expression has an impact on the clinical
                      outcome of patients with {H}ead-and-neck {S}quamous {C}ell
                      {C}arcinoma undergoing {C}hemoradiation.},
      journal      = {Theranostics},
      volume       = {10},
      number       = {20},
      issn         = {1838-7640},
      address      = {Wyoming, NSW},
      publisher    = {Ivyspring},
      reportid     = {DKFZ-2020-01681},
      pages        = {9395 - 9406},
      year         = {2020},
      note         = {2020 Jul 23;10(20):9395-9406},
      abstract     = {Tumor-associated hypoxia influences the radiation response
                      of head-and-neck cancer (HNSCC) patients, and a lack of
                      early hypoxia resolution during treatment considerably
                      deteriorates outcomes. As the detrimental effects of hypoxia
                      are partly related to the induction of an immunosuppressive
                      microenvironment, we investigated the interaction between
                      tumor hypoxia dynamics and the PD-1/PD-L1 axis in HNSCC
                      patients undergoing chemoradiation and its relevance for
                      patient outcomes in a prospective trial. Methods: 49
                      patients treated with definitive chemoradiation for locally
                      advanced HNSCC were enrolled in this trial and received
                      longitudinal hypoxia PET imaging using fluorine-18
                      misonidazole ([18F]FMISO) at weeks 0, 2 and 5 during
                      treatment. Pre-therapeutic tumor biopsies were
                      immunohistochemically analyzed regarding the PD-1/PD-L1
                      expression both on immune cells and on tumor cells, and
                      potential correlations between the PD-1/PD-L1 axis and tumor
                      hypoxia dynamics during chemoradiation were assessed using
                      Spearman's rank correlations. Hypoxia dynamics during
                      treatment were quantified by subtracting the standardized
                      uptake value (SUV) index at baseline from the SUV values at
                      weeks 2 or 5, whereby SUV index was defined as ratio of
                      maximum tumor [18F]FMISO SUV to mean SUV in the
                      contralateral sternocleidomastoid muscle (i.e.
                      tumor-to-muscle ratio). The impact of the PD-1/PD-L1
                      expression alone and in combination with persistent tumor
                      hypoxia on locoregional control (LRC), progression-free
                      survival (PFS) and overall survival (OS) was examined using
                      log-rank tests and Cox proportional hazards models. Results:
                      Neither PD-L1 nor PD-1 expression levels on
                      tumor-infiltrating immune cells influenced LRC (HR = 0.734;
                      p = 0.480 for PD-L1, HR = 0.991; p = 0.989 for PD-1), PFS
                      (HR = 0.813; p = 0.597 for PD-L1, HR = 0.796; p = 0.713 for
                      PD-1) or OS (HR = 0.698; p = 0.405 for PD-L1, HR = 0.315; p
                      = 0.265 for PD-1). However, patients with no hypoxia
                      resolution between weeks 0 and 2 and PD-L1 expression on
                      tumor cells, quantified by a tumor proportional score (TPS)
                      of at least $1\%,$ showed significantly worse LRC (HR =
                      3.374, p = 0.022) and a trend towards reduced PFS (HR =
                      2.752, p = 0.052). In the multivariate Cox regression
                      analysis, the combination of absent tumor hypoxia resolution
                      and high tumoral PD-L1 expression remained a significant
                      prognosticator for impaired LRC (HR = 3.374, p = 0.022). On
                      the other side, tumoral PD-L1 expression did not compromise
                      the outcomes of patients whose tumor-associated hypoxia
                      declined between week 0 and 2 during chemoradiation (LRC: HR
                      = 1.186, p = 0.772, PFS: HR = 0.846, p = 0.766). Conclusion:
                      In this exploratory analysis, we showed for the first time
                      that patients with both persistent tumor-associated hypoxia
                      during treatment and PD-L1 expression on tumor cells
                      exhibited a worse outcome, while the tumor cells' PD-L1
                      expression did not influence the outcomes of patients with
                      early tumor hypoxia resolution. While the results have to be
                      validated in an independent cohort, these findings form a
                      foundation to investigate the combination of hypoxic
                      modification and immune checkpoint inhibitors for the
                      unfavorable subgroup, moving forward towards personalized
                      radiation oncology treatment.},
      cin          = {FR01 / E055},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331 / I:(DE-He78)E055-20160331},
      pnm          = {315 - Imaging and radiooncology (POF3-315)},
      pid          = {G:(DE-HGF)POF3-315},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32802199},
      pmc          = {pmc:PMC7415814},
      doi          = {10.7150/thno.48392},
      url          = {https://inrepo02.dkfz.de/record/157525},
}